Funding of this application will move a new combination cancer therapy for leukemia and lymphomas towards human clinical trials. Monoclonal antibodies, mAbs have emerged as a rapidly growing class of oncology therapeutics. Despite their success in certain clinical applications, the therapeutic efficacy of mAbs is limited, with only a minority of patients responding to these agents as therapies on their own. It is becoming clear that many tumors evade successful elimination by co-opting the body's own immune regulatory systems. These same mechanisms also reduce the anti-cancer effects of mAbs. We are developing a molecule that addresses one of these key mechanisms that improves the therapeutic effects of mAbs by: 1) increasing sensitivity of cancers to treatment; 2) unmasking resistant cancers so they again become sensitized; and 3) possibly allowing treatment of cancers that have become refractory to therapy. This could make mAb therapy more effective, and potentially reduce the amounts of mAbs required for treatment, thus reducing costs and potential side effects. The public health implications of improving rituximab treatment are significant. There are over 300,000 patients with non-Hodgkins lymphoma (NHL), and the majority receives treatment with rituximab either alone or combined with chemotherapy. Many patients develop recurrent diseases, and 5-year survival rates for NHL is 63%. In most cases of tumor recurrence, patients develop resistance to rituximab therapy. The immediate goal of the research is to collect data to enable an Investigational New Drug (IND) filing on a combination therapy for lymphoma. Our consultant at the University of Washington has collected a significant body of information supporting the superiority of the combination of depleting CD46 on the cell surface with antibody therapy in blood cancers Our long-term goal is to translate the technology from research bench to clinical bedside leading to enhancement of monoclonal antibody (mAb) therapy.